The Role of Orexin/hypocretin on Circadian Rhythm in a Temporal Lobe Epilepsy (TLE) Rat
Date Issued
2010
Date
2010
Author(s)
Chen, Ying-Ju
Abstract
Epilepsy is a chronic disorder characterized by recurrent seizures, which may vary from a brief lapse of attention or muscle jerks to severe and prolonged convulsions. It was caused by sudden, brief, excessive electrical discharges in a group of brain cells. Clinical and experimental observations suggest that the relationship between sleep and epilepsy is reciprocal. Excessive daytime sleepiness and sleep complaints are common among epilepsy patients, which implies the influence of epilepsy on circadian rhythm. However, little is known about this interaction. Amygdala kindling-induced temporal lobe epilepsy (TLE) in rats was used in current study to mimic the patients with epilepsy. Suprachiasmatic nucleus (SCN) of anterior hypothalamus is the pacemaker controlling circadian rhythm. The circadian oscillation is driven by clock genes in the SCN, including per1, per2, per3, cry1, cry2, CLOCK, and bmal1. Circadian oscillation of per1 peaks at subjective day and in antiphase to bmal1 expression, which peaks at subjective night. In addition, the lateral hypothalamic area (LHA), which received afferents from the central nucleus of amygdala (CeA), involves in the homeostatic regulation of sleep-wake rhythmicity. The neuropeptide secreted form LHA is orexin/hypocretin, which is as a waking promoter. Moreover, orexinergic/hypocretinergic fibers and receptor expressions are detected in the SCN region. Therefore, we investigated the role of hypocretin in TLE-induced sleep alternations by pharmacological blockade of hypocretin receptor 1 and determined the expressions of PER1 in SCN between the normal and TLE rats.
Male Sprague-Dawley rats were housed in a 12:12-hour light:dark cycle. Kindling stimuli delivered via a bipolar electrode, placing in the right central nucleus of the amygdala, at circadian time 6 (CT 6). We injected orexin receptor 1 / hypocretin receptor 1 antagonist, SB334867, into the SCN of the TLE rats. Electroencephalogram (EEG) and movement-defined sleep-wake activity were collected. The other group, rats received a single stimulus at CT6. At the following circadian time points, CT18 and the next CT0, CT3, CT6, CT9 and CT12, normal and TLE rats were sacrificed and their brains were processed for immunohistochemical detection of PER1.
The amount of non-rapid eye movement sleep (NREMS) after CT 6 amygdala-kindling was increased from 9.56 ± 3.37 % after vehicle to 27.36 ± 4.71 % during the CT23-24. There was a mirrored reduction in the amount of wakefulness. The amount of NREMS during the subsequent CT11-12 was decreased from 42.81 ± 4.16 % after vehicle to 18.97 ± 3.15 % after CT6 amygdala-kindling. There was also a mirrored increase in the amount of wakefulness. The alterations of NREMS after CT 6 amygdala-kindling were blocked when orexin receptor 1 / hypocretin receptor 1 antagonist, SB334867, was administered. Besides, SB334867 administration at CT 6 in normal rats didn’t have effect on spontaneous NREMS. In addition, the control group exhibited maximal values for PER1 at CT 12, and the CT 6 kindling group peaked at CT 6. PER1-positive cells in the CT 6 kindling group increased from 358 ± 64 to 147 ± 14 compared to the control group at CT 6.
The CT 6 amygdala kindling results in the circadian phase shifts with a 2-hour advance. However, the circadian alteration was blocked by microinjection of hypocretin receptor1 antagonist into SCN. This result suggests that circadian phase shift induced by CT 6 amygdala kindling is mediated by orexin/hypocretin.
Subjects
temporal lobe epilepsy (TLE)
sleep
circadian rhythm
PER1
Type
thesis
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